Endosseous implant

ABSTRACT

Endosseous implant to be applied to human or animal bone, said implant having a surface made from a selected metal or a selected metal alloy or a ceramic, whereby said resp, metal alloy is selected from chromium, niobium, tantalum, vanadium, zirconium, aluminium, cobalt, nickel, stainless steels or an alloy thereof, said surface having a smooth or rough texture, characterized in that said surface has been treated with at least one pharmaceutically acceptable organic compound carrying at least one phosphonic acid group or a derivative thereof preferably acceptable salt or ester or amid thereof and method for producing said implant.

[0001] The present invention relates to a selected metallic or selectedceramic endosseous implant to be applied to a human or animal bone, saidimplant having a smooth or rough surface texture, and wherein saidsurface has been treated with at least one selected organic compoundcarrying at least one phosphonic acid group or a derivative thereof.

[0002] Selected metallic surfaces within the meaning of the presentinvention are made from metals such as chromium, niobium, tantalum,vanadium, zirconium, aluminium, cobalt, nickel, stainless steels oralloys thereof. Excluded are metallic titanium and metallic titaniumalloy surfaces.

[0003] Ceramic surfaces within the meaning of the present invention arepreferably made from a metal oxide, metal carbide, metal nitride, metaloxynitride, metal carbonitride and/or metal oxycarbide. Examples of suchmetal oxides, carbides, nitrides, oxynitrides, carbonitride oroxycarbides are those of chromium, niobium, tantalum, vanadium,zirconium, aluminium, cobalt, nickel, stainless steels or alloysthereof, included also titanium carbide, titanium nitride, titaniumoxynitride, titanium carbonitride and/or titanium oxycarbide.

[0004] Implants according to the present invention may be used asprostheses in medicine, more specifically in orthopaedics, for replacingor strengthening broken or diseased bones, and in dentistry, foranchoring artificial teeth and for anchoring of bone anchored hearingprosthesis. It has been shown that surfaces modified according to thepresent invention surprisingly enhance the bone bonding strength.

[0005] Implants which are used as prostheses in medicine for replacingor strengthening broken or diseased bones or as artificial teeth areknown. These implants must be made of a non-corrosive material and mustbe compatible with the surrounding tissue without producing immunologicreactions effecting rejection by the body. In the following the terms“surface” or “contact surface” refer to the defined metallic or ceramicimplant surface not yet treated according to the present invention andthe term “modified surface” to said surface treated according to thepresent invention.

[0006] It is known that implanting devices in the form of screws,plates, nails, pins, and specially formed parts into the skeletalstructure of humans and animals as artificial prosthetic is a means forpermanent replacement of missing structural parts or as permanentanchoring devices. An excellent “osseointegration” is required for thosesituations where the implanted device should remain permanently adheredto the contacting bone surface.

[0007] It is known to use selected metals and selected ceramic materialsfor implants. When carefully produced, the implant with its surfaceexhibits biocompatibility in the sense that it remains passive for boneregeneration and does not per se induce adverse reactions such asinflammation or soft tissue generation or encapsulation. The interfaceobtained between the implant and the bone tissue normally consists of aprotein layer of about 100 nm to 1 μm thickness preventing the bonetissue from being in direct molecular contact with the implant.

[0008] The actual state of the art for endosseous implants is based ondifferent approaches, for example (i) the creation of a suitableroughness of the implant surface giving a mechanical interlockingbetween bone and implant and/or (ii) coating the surface of the implant,e.g. with an artificial hydroxyapatite for improving the healing processand the bone-implant intimate contact.

[0009] It is known that a high surface roughness increases themechanical stability of the implant in the bone tissue. Mechanicalsurface treatment significantly alters the topography, while the surfacechemistry remains substantially unchanged. The disadvantages of animplant with a high surface roughness are that a purely mechanicalanchoring is very sensible to micromotions which may lead to adeterioration of the mechanical anchorage and that the osseointegrationtime of the implant is relatively long.

[0010] Coating the surface of the implant with an artificialhydroxyapatite decreases the osseointegration time. However, it is verydifficult, if not impossible, to produce hydroxyapatite coatings with along term stability on load bearing implants. The interface between thecoating and the implant is often disrupted or the coatings are flakedoff.

[0011] It has now been found that if the surface of an endosseousimplant which has a selected metallic or ceramic surface as definedherein is treated with at least one organic compound carrying at leastone phosphonic acid group [—P(O)(OH)₂] or a derivative thereof, asdefined herein below, said surface shows a surprisingly improved bonebonding strength and a surprisingly shortened osseointegration timecompared to the non treated surface and does not have the disadvantagesas known for surfaces having a hydroxyapatite coating.

[0012] The present invention is defined in the claims. The presentinvention specifically refers to an endosseous implant to be applied toa human or animal bone, said implant having a surface made from aselected metal or a selected metal alloy or a ceramic, whereby saidmetal resp. metal alloy is selected from chromium, niobium, tantalum,vanadium, zirconium, aluminium, cobalt, nickel, stainless steels or analloy thereof, said surface having a smooth or rough texture,characterized in that said surface has been treated with at least onepharmaceutically acceptable organic compound carrying at least onephosphonic acid group or a derivative thereof, which is preferably apharmaceutically acceptable ester or amide or a salt thereof.

[0013] The present invention further refers to a process for producingthe implant according to the present invention, which is characterizedin that said surface is treated with at least one pharmaceuticallyacceptable organic compound carrying at least one phosphonic acid groupor a derivative thereof preferably an ester or an amide or a saltthereof.

[0014] The metallic surface of the endosseous implant to be treatedaccording to the present invention is made from chromium, niobium,tantalum, vanadium, zirconium, aluminium, cobalt, nickel, stainlesssteels or an alloy thereof. Such metals and metal alloys for makingimplants are described for example in Breme et al., Metals asbiomaterials, pp. 1-71 (1998), John Wiley & Sons Ltd, Chichester,England; J. B. Park and R. S. Lakes, Biomaterials, An Introduction(1992), 2nd Edition, Plenum Press, New York) pp. 79-115 and 293-354; R.Schmidt, Comportement des matériaux dans les milieux biologiques,Applications en médecine et biotechnologie, Vol. 7 (1999) pp. 294-343,Presses polytechniques et universitaires romandes, Lausanne,Switzerland, the relevant contents of which are incorporated herein byreference.

[0015] Alternatively, the surface of the endosseous implant to betreated according to the present invention may be made of a ceramic.Such ceramic surfaces are for example metallic surfaces which have beentreated thermally or chemically or treated with a plasma or anotherappropriate method. Such treatments are known and have been described inthe literature, such as oxide surfaces, carbide surfaces, nitridesurfaces, oxynitride surfaces, carbonitride surfaces or oxycarbidesurfaces, for example those of chromium, niobium, tantalum, vanadium,zirconium, aluminium, cobalt, nickel, stainless steels or alloysthereof. Included are titanium carbide, titanium nitride, titaniumoxynitride, titanium carbonitride and/or titanium oxycarbide. Excludedfrom the present invention are surfaces made from titanium oxide.

[0016] Such surfaces and their production is known and is described forexample in H. Bender et al., Surf. Interface Anal. 14 (1989) pp. 337fs.Preferred ceramic surfaces which are made from metal oxides, arealuminium oxide or zirconium oxide or silicon oxide, preferably fromapatites, preferably hydroxyapatite or fluoroapatite, or apatite likematerials, preferably tricalciumphosphate, or brushite type layers suchas are described for example in Breme et al., Metals as biomaterials,pp. 219-264 (1998), ed. J. A. Helsen et al., John Wiley & Sons Ltd,Chichester, England; or J. B. Park and R. S. Lakes, Biomaterials, AnIntroduction (1992), 2nd Edition, Plenum Press, New York, pp. 117-140and 169-183; or R. Schmidt, Comportement des matériaux dans les milieuxbiologiques, Applications en médecine et biotechnologie, Vol. 7 (1999),pp. 306-314, Presses polytechniques et universitaires romandes,Lausanne, Switzerland).

[0017] Other ceramic surfaces which may be used within the scope of thepresent invention may be glass like surfaces made for example fromsilicate glass, or boron silica glass, or bioglass such as described forexample in R. Schmidt, Comportement des matériaux dans les milieuxbiologiques. Applications en médecine et biotechnologie, Vol. 7 (1999),pp. 306-314, Presses polytechniques et universitaires romandes,Lausanne, Switzerland as well as in other literature references citedabove. the contents of which are incorporated herein by reference.

[0018] Preferred organic compounds to be used within the scope of thepresent invention have at least one phosphonic acid group or aderivative thereof, which is preferably an ester or an amide or a saltthereof, resp. preferred implants have a surface which has been treatedwith at least one organic compound, or a mixture of such compounds,corresponding to the general formula (I):

A—[P(O)(OH)₂]_(P)  (I),

[0019] or a pharmaceutically acceptable derivative thereof, which ispreferably an ester or an amide or a salt thereof, wherein A means A₁ orA₂, and

[0020] A₁ is a residue of a linear, branched or cyclic, saturated orunsaturated, hydrocarbon residue with n carbon atoms, whereby saidresidue may be substituted by hydroxyl and/or carboxyl and optionallyfurther interrupted by one or more oxygen and/or sulphur and/or nitrogenatoms, carrying p phosphonic acid groups, wherein

[0021] n is a number from 1 to 70, preferably 1 to 40, preferably 1 to22, and

[0022] p is 1, 2, 3, 4, 5 or 6, preferably 1, 2, 3, 4 or 5, preferably1, 2, 3 or 4; or

[0023] or A means A₂ and A₂ is a residue of an amino acid or of asequence of amino acids resp. of a protein or of a polypeptide,preferably a residue of the superfamily of Transforming Growth Factorbeta (TGF-β); or a residue of a specific drug molecule, wherein eachresidue A₂ carries p phosphonic acid groups, and

[0024] p is 1 to 6, preferably 1, 2, 3 or 4, preferably 1, 2, or 3, whenA₂ is a residue of an amino acid or of a sequence of amino acids resp.of a protein or of a polypeptide; or

[0025] p is 1, 2, 3, 4, 5 or 6, preferably 1, 2 or 3, and preferably 1,when A₂ is a residue of a specific drug molecule originally not bearingany phosphonic group, optionally falling under the definition given forA₁.

[0026] Compounds (i) and (ii) of the general formula (I) are preferred:

[0027] (i) If A has a meaning of A₁, then: when n is 1 and p is 2: A ispreferably —CH₂—; or when n is 1: p is preferably 3 or 4, preferably 3;or when n is 2 to 10: p is preferably 2, provided each phosphonic acidgroup or phosphonic acid ester group or phosphonic acid amide group isbound to a different carbon atom within the same molecule; or when n is2 to 10: p is preferably 3, 4, 5 or 6, preferably 3, 4 or 5, preferably3 or 4; or when n is 11 to 70: p is preferably 2, 3, 4, 5 or 6,preferably 2, 3, 4 or 5, preferably 2, 3 or 4.

[0028] (ii) If A has the meaning of A₂, then: p is preferably 1 or 3-6,preferably 1, for the case that A₂ is a residue of a specific drugmolecule originally not bearing any phosphonic group, optionally fallingunder the definition given for A₁.

[0029] It is assumed that the phosphonate compounds as specified herein,especially as acids or salts, form a covalent bond with the surface ofthe implant thereby improving the osseointegration properties of saidsurface to a remarkable and unexpected extent. The present inventionhowever is not bound to this explanation.

[0030] A₁ preferably is a saturated hydrocarbon residue of the formula—(C_(n)H_(2n+2−p))—, wherein n means 1 to 70, preferably 1 to 40,preferably 1 to 22. Preferred is the free acid or the salt form of thecompound of formula (I), preferably where the pharmaceuticallyacceptable salt is an alkali salt, preferably of sodium or potassiumsalt.

[0031] Examples of compounds of formula (I) wherein A₁ is a residue of asaturated hydrocarbon [e.g. an alkyl chain with 1 to 70 carbon atoms(C₁-C₇₀-Alkyl)] are monophosphonic acids such as methanephosphonic acid,ethanephosphonic acid, propane-phosphonic acid or polyphosphonic acidssuch as methylenediphosphonic acid, ethane-1,2-diphosphonic acid,propane-1,3-diphosphonic acid, ethane-1,1,2-triphosphonic acid,propane-1,1,3-triphosphonic acid, butane-1,1,4-triphosphonic acid,pentane-1,1,5-triphosphonic acid, pentane-2,2,5-triphosphonic acid,hexane-2,2,6-triphosphonic acid, pentane-1,1,5,5-tetraphosphonic acid,heptane-1,4,4,7-tetraphosphonic acid, propane-1,1,3,3-tetraphosphonicacid, or nonane-1,5,5,9-tetraphosphonic acid.

[0032] Examples of compounds of formula (I) wherein A₁ is a residue ofan unsaturated hydrocarbon are unsaturated monophosphonic acids andpolyphosphonic acids such as those given in H.

[0033] Fleisch, Bisphosphonates in bone disease, from the laboratory tothe patient 2000, 4rd edition, The Parthenon Publishing Group, p.31-33,which compounds are incorporated herein by reference.

[0034] If the pharmaceutically acceptable ester is used, the isopropylphosphonate or ethyl phosphonate esters, preferably of the acids givenin the two previous chapters, are preferred. Further examples of suchesters are: tetra isopropyl methylenediphosphonate, hexaethylethane-1,1,2-triphosphonate, hexaisopropyl butane-1,1,4-triphosphonate,hexaisopropyl pentane-1,1,5-triphosphonate, hexaisopropylpentane-2,2,5-triphosphonate, hexaisopropyl hexane-2,2,6-triphosphonate,octaisopropyl propane-1,1,3,3-tetraphosphonate, octaisopropylheptane-1,4,4,7-tetraphosphonate, octaisopropylnonane-1,5,5,9-tetraphosphonate.

[0035] Examples of compounds of formula (I) wherein A₂ is a residue of aprotein resp. polypeptide are compounds in the form of a TransformingGrowth Factor beta (TGF-β) in which are included the all members of thesuperfamily of growth factors and particularly the TGF-β1, TGF-β2,TGF-β3, TGF-β4, and TGF-β5 as described for example in A. B. Roberts, M.B. Sporn, Handbook of Experimental Pharmacology, 95 (1990) pp. 419-472or D. M. Kingsley, Genes and Development 8 (1994) p. 133-146, andreferences therein, where the peptide chain has been modified to containan alkylphosphonic acid group or a derivative thereof preferably anester or an amide or a salt thereof. In this sense the compound offormula (I) represents a Transforming Growth Factor beta (TGF-β) asdefined by the members of the superfamily of growth factors, preferablythe TGF-β1, TGF-β2, TGF-β3, TGF-β4, and TGF-β5, wherein each time thepeptide chain has been modified to contain at least one alkylphosphonicacid group or a derivative thereof preferably an ester or an amide or asalt thereof.

[0036] Examples of compounds of formula (I) wherein A is a residue of aBone Morphogenic Protein (BMP) (being a subfamily to the TGF family) arecompounds e.g., the BMP-2 (BMP-2a), BMP-3, BMP-4 (BMP-2b), BMP-5, BMP-6,BMP-7 (OP-1), BMP-8 (OP-2), BMP-9, BMP-10, BMP-11, BMP-12, BMP-13, asfound for example in J. M. Wozney et. al., Science 242 (1988) 1528-1534;A. J. Celeste et al., Proc. Natl. Acad. Sci. USA 87 (1990) 9843-9847; E.Özkaynak et al., J. Biol. Chem. 267 (1992) 25220-25227; Takao et al.,Biochem. Biophys. Res. Com. 219 (1996) 656-662 ; WO 93/00432 ; WO94/26893 ; WO 94/26892 ; WO 95/16035 and references therein, where thepeptide chain has been modified to contain an alkylphosphonic acid groupor a derivative thereof preferably an ester or an amide or a saltthereof. These compounds are incorporated herein by reference. In thissense the compound of formula (I) represents a Bone Morphogenic Protein(BMP), preferably the BMP-2 (BMP-2a), BMP-3, BMP-4 (BMP-2b), BMP-5,BMP-6, BMP-7 (OP-1), BMP-8 (OP-2), BMP-9, BMP-10, BMP-11, BMP-12,BMP-13, wherein the peptide chain has been modified to contain at leastone alkylphosphonic acid group or a derivative thereof preferably anester or an amide or a salt thereof.

[0037] Examples of compounds of formula (I) wherein A₂ is a residue ofan amino acid are 2-amino-4,4-bis-(diethoxy-phosphoryl)-butyric acid asdescribed for example in O. Fabulet et al., Phosphorus, Sulphur Siliconand Related Elements, 101, 225-234 (1995);2-amino-5-(diethoxy-phosphoryl)-pentanoic acid as described for examplein I. G. Andronova et al., Russ. J. Gen. Chem. 66, 1068-1071 (1996);2-amino-4-phosphonobutyric acid as described for example in X. Y. Jiaoet al., Synth. Commun. 22, 1179-1186 (1992) and references therein.Further examples are all the principal twenty amino acids as describedfor example in L. Stryer, Biochemistry, 3rd edition (1988), pp. 17-22,where the amino acid is modified in an analogous way with analkylphosphonic acid group, preferably wherein the compound of formula(I) is one of the principal twenty amino acids, preferably arginine,glycine, aspartic acid, alanine, valine, proline, serine, threonine,cysteine or lysine, wherein the amino acid has been modified to containat least one alkylphosphonic acid group or a derivative thereofpreferably an ester or an amide or a salt thereof. These compounds areincorporated herein by reference.

[0038] Examples of compounds of formula (I) wherein A₂ is a residue of apeptide comprise but are not limited to RGD-containing peptides,RGDS-peptides, GRGDS-peptides, RGDV-peptides, RGDE-peptides, and/orRGDT-peptides. Such peptides are described for example in Y. Hirano, J.Biomed. Materials Res., 25 (1991), pp. 1523-1534 or in WO 98/52619 andreferences therein. Included within the scope of the present inventionare also similar peptides known to have specific biological activitiessuch as cell attachment or cell attachment prevention, and which areprepared in analogy with the peptides as mentioned above. In this sensethe compound of formula (I) is a RGD-containing peptide, preferably aRGDS-peptide, a GRGDS-peptide, a RGDV-peptide, a RGDE-peptide, and/or aRGDT-peptide, which has been modified to contain at least onealkylphosphonic acid group or a derivative thereof preferably an esteror an amide or a salt thereof.

[0039] Examples of compounds of formula (I) wherein A₂ is a residue of aspecific drug molecule are 1-hydroxy-3-(1-pyrrolidinyl)-propylidenediphosphonic acid, or cycloheptylamino-methylene diphosphonic acid, or1-hydroxy-2-imidazo-(1,2-a)-pyridin-3-yl-ethylidene diphosphonic acid or1-hydroxy-2-(3-pyridinyl)-ethylidene diphosphonic acid or(4-chlorophenyl)thio-methylene diphosphonic acid or1-hydroxy-2-(1H-imidazole-1-yl)ethylidene diphosphonic acid and relatedcompounds as described for example in H. Fleisch, Bisphosphonates inbone disease, from the laboratory to the patient 2000, 4rd edition, TheParthenon Publishing Group, pp. 31-33, and references therein. Suchcompounds are included herein by reference.

[0040] Preferred compounds of formula (I) are those containing a residueA₂ as defined above, preferably a residue of an amino acid or of asequence of amino acids resp. of a protein or of a polypeptide,preferably a residue of the superfamily of Transforming Growth Factorbeta (TGF-β), preferably a Bone Morphogenic Protein (BMP).

[0041] The following steps are recommended to be taken for producing theimplant according to the present invention, i.e. for treating thesurface of the implant with at least one compound of formula (I) or amixture of these compounds. The implant is first cleaned in a cleaningbath for removing unwanted molecules resp. impurities from the surface.Preferably the implant is first treated with a degreasing agent, forexample an organic solvent such as alcohol, chloroform, and anotherorganic solvent and/or an inorganic detergent such as an aqueousalkaline solution based on sodium hydroxide or potassium hydroxide.Subsequently, the implant is carefully rinsed in pure water, preferablyin distilled ultra-pure water, having preferably a conductivityresistance of at least 15 Mohm*cm. After cleaning and rinsing, theimplant is dried with flowing nitrogen gas or flowing dry or hot air andstored under controlled conditions. Alternatively after degreasing theimplant can be further treated in a glow-discharge plasma for cleaningthe surface. The clean surface of the implant is then treated with atleast one compound of formula (I) or an ester or a salt thereof, i.e.with at least one such compound or a mixture of such compounds. Thecompound or the mixture of said compounds is brought onto the surface ofthe implant by any suitable means, like brushing, spraying, dipping or,evaporation, including glow-discharge plasma assisted vapour deposition.The phosphonic acid compound or the ester or the salt thereof ispreferably dissolved in a polar solvent, so that a solution with aconcentration of from about 1.0×10⁻⁵ mol/10 ml to 5×10² mol/10 ml,preferably from about 5×10⁻⁴ mol/10 ml to 2.0×10⁻² mol/10 ml withreference to the weight of the solvent is obtained. Preferably theconcentration is such that a partial or full (1% to 100%, preferably 50%to 100% of a) monomolecular layer is formed on the implant surface. Thepreferred solvent is pure distilled water. The implant is left incontact with the solution for a sufficiently long time, preferably for afew minutes up to a few hours. After that the implant is carefullyrinsed with pure water and packed with a plastic or metallic cleanpackaging material preferably into an air tight packaging whichpreferably is evacuated or filled with an inert gas such as nitrogen oran inert liquid such as pure water as defined herein above. Said purewater may contain inorganic salts, preferably alkali salts, such asalkali chlorides, sulphates, phosphates, phosphonates, preferably thesodium and/or potassium salts, and/or compounds of the formula (I) or anester or a salt thereof, which is preferably in a concentration of fromabout 1.0×10⁻⁵ mol/10 ml to 5×10⁻² mol/10 ml, preferably from about5×10⁻⁴ mol/10 ml to 2.0×10⁻² mol/10 ml of solvent, which preferably isdistilled water.

[0042] Analytical investigations, e.g. X-ray Photoelectron Spectros-copyanalysis (XPS) or NMR, have shown that on contacting the phosphonic acidcompound of formula (I) with the surface of the implant, immediateadsorption takes place. A strong bond is formed between the surface andthe phosphonic acid compound so that a chemical surface modification isobtained. Several different polyphosphonic acids, salts, esters andamides as mentioned herein above were synthesized. Dental implantsproduced with these compounds according to the present invention haveshown excellent results.

[0043] Implants according to the present invention may be in the form ofscrews, plates, nails, pins, and specially formed parts and may be usedas prostheses in medicine, more specifically in orthopaedics, forreplacing or strengthening broken or diseased bones, and in dentistry,for anchoring artificial teeth and for anchoring of bone anchoredhearing prosthesis into the skeletal structure of humans and animals.The surface area of the implant which is to be bound to the body tissueresp. bones, may have a smooth or rough surface texture. Such surfacetextures are known and can be obtained for example by treating thesurface mechanically and/or with acids and/or electrolytically and/orwith a glow-discharge plasma and/or plasma spraying and/or or by electromachining. Such materials and processes have been described in differentpublications, for example in B.-O. Aronsson et al., J. Biomed. Mater.Res. 35 (1997), pp. 49f., the contents of which are incorporated hereinby reference.

[0044] The compounds according to the general formula (I), wherein p is3 to 6, preferably 3 or 4, and n is 4 to 70, preferably 4 to 40,preferably 4 to 22, the salts or esters or amides thereof are new.Examples of such compounds are butane-1,1,4-triphosphonic acid,pentane-1,1,5-triphosphonic acid, pentane-2,2,5-triphosphonic acid,hexane-2,2,6-triphosphonic acid, pentane-1,1,5,5-tetraphosphonic acid,heptane-1,4,4,7-tetraphosphonic acid, or nonane-1,5,5,9-tetraphosphonicacid.

[0045] The compounds hexaisopropyl butane-1,1,4-triphosphonate andoctaisopropyl heptane-1,4,4,7-tetraphosphonate, resp. a mixture of thesecompounds, are obtained in that an alkalimetal, preferably sodium, tetralower alkyl methylenediphosphonate, preferably tetraisopropylmethylenediphosphonate, is reacting with at least a stoichiometricamount of a dihalomethane, preferably dibromomethane, in the presence ofan organic solvent having no active hydrogen atoms, preferably dryhexane or benzene or toluene.

[0046] The reaction is preferably carried out at a temperature withinthe range of 30° C. to 125° C., preferably 40° C. to 110° C., until thereaction is completed, which generally is within a time period of 10 to48 hours, preferably 18 to 36 hours.

[0047] To the reaction product is then added the purified product oftriisopropylphosphite that has been reacted withdiisopropyl-3-bromopropane. The obtained mixture of compounds can thenbe separated in a conventional manner, for example by columnchromatography.

[0048] In an analogous way, by reacting 1,4-dibromobutane in excessmolar ratio in the range 1:6 to 1:0.5 with triisopropylphosphite,surprisingly the new compounds hexaisopropylpentane-1,1,5-triphosphonate and octaisopropylnonane-1,5,5,9-tetraphosphonate are produced. Further, in an analogousway the hexaisopropyl pentane-2,2,5-triphosphonate and hexaisopropylhexane-2,2,6-triphosphonate were obtained by reacting equal parts oftetraisopropylethane-1,1-diphosphonate withdiisopropyl-3-bromopropylphosphonate.

[0049] The process is further characterised by that these products arehydrolysed to produce the analogous acids by refluxing them in molarexcess of HCl for a time comprised within 1 to 12 hours, preferably 1 to6 hours. The compounds are then preferably dried under vacuum over P₂O₅.

[0050] The following Examples illustrate but do not limit the presentinvention.

EXAMPLE 1

[0051] (Synthesis of Alkane Polyphosphonic Acids)

[0052] Methylenediphosphonic acid was synthesized according to U.S. Pat.No. 3,400,176 and B. A. Arbusov, Pure Appl. Chem. 9 (1967), pp. 307-353and references therein. The compound was characterized by NMR (¹H, ³¹P,¹³C) mass spectroscopic elemental analysis and by its melting point. Allthese data are in accordance with the literature O. T. Quimby et al.,Metalated methylendiphosphonate esters, preparation, characterizationand synthetic applications, J. of Organomet. Chem. 13, 199-207 (1968).

[0053] Propane-1,1,3,3-tetraphosphonic acid was synthesized fromtetraisopropyl methylenediphosphonate. The tetraphosphonic acidicsolution was concentrated under vacuum, dried over P₂O₅ under vacuum.The ¹H, ³¹P and ¹³C NMR results (D₂O) are in accordance with the givenliterature data.

[0054] In an analogous manner propane-1,3-diphosphonic acid,ethane-1,1,2-triphosphonic acid, butane-1,1,4-triphosphonic acid,pentane-1,1,5-triphosphonic acid, pentane-2,2,5-triphosphonic acid,hexane-2,2,6-triphosphonic acid, pentane-1,1,5,5-tetraphosphonic acid orheptane-1,4,4,7-tetraphosphonic acid, are synthesized.

EXAMPLE 2

[0055] A) A dental implant made from titanium in the form of a screw,having a diameter of 4 mm and a length of 10 mm, is produced in aconventional manner. The surface to be implanted into the body isprovided with a surface roughness according to EP 0 388 575 bysandblasting the surface using an average grain size of 0.25-0.5 mm,followed by a treatment with a mixture of an aqueous acidic mixturecontaining a mixture of hydrochloric acid/sulfuric acid/water in a ratioof 2:1:1, at a temperature of about 80° C. for about 5 minutes so that arough surface of the implant is obtained which is about 3.6 times largercompared to the polished surface, as measured with the voltametricmethod in aqueous electrolyte with 0.15M NaCl. The surface of theimplant is then chemically treated with a nitrogen plasma to yield atitanium nitride surface as described in B.-O. Aronsson et al., J.Biomed. Mater. Res. 35 (1997), pp. 49f. The treated implant, resp.surface, is sonicated in bidistilled water during 15 minutes at 30° C.,washed with pure water followed by sonication in water (three times) for10 minutes and then rinsed with pure hexane and dried under vacuum (10mm Hg, room temperature).

[0056] B) The implant as produced in chapter A) above is then put intoan aqueous solution of (i) methylenediphosphonic acid [1,5×10⁻³ mol per10 ml of distilled water], (ii) ethane-1,1,2-triphosphonic acid[6.2×10⁻⁴ mol/10 ml, in distilled water], (iii)pentane-1,1,5-triphosphonic acid [1.2×10⁻⁴ mol/10 ml, in distilledwater], (iv) pentane-1,1,5-triphosphonic acid potassium salt [1.2×10⁻⁴mol/10 ml, in distilled water] and left there at room temperature for 15minutes. The implant is then rinsed with pure water.

[0057] The implant prepared according to the preparations B(i), B(ii),B(iii) and B(iv) are implanted into the upper jaw of a mini pig. Theosseointegration is measured as the torque needed to unfasten theimplant from the jaw where it had osseointegrated. Comparative testresults are given for the untreated implant. The results are given inTable 1. Analogous results are obtained for further phosphonic acidsgiven herein above. Analysis with XPS and ToF-SIMS indicated that amolecular (mono) layer was formed on the implant surface as well as onthe titanium nitride surface, and that the roughness of the surface didnot seem to influence this behaviour. TABLE 1 Torque* after 2 torque*after 3 torque* after 4 Preparation weeks (Ncm) weeks (Ncm) weeks (Ncm)B(i) 31 72 130 B(ii) 30 80 125 B(iii) 32 79 132 B(iv) 29 83 124Comparative 20 60 100 Test

[0058] The results illustrate the improved osseointegration of theimplants according to the present invention compared to the non treatedimplants.

EXAMPLE 3

[0059] Example 2 is repeated with the difference that the originaltitanium surface of the implant is treated with methane in an argon glowdischarge plasma so that a surface of titanium carbide is obtained. Thetreatment is performed as described in B.-O. Aronsson et al., J. Biomed.Mater. Res. 35 (1997), pp. 49f. Analogous test results are obtainedanalogous to those given in Table 1.

EXAMPLE 4

[0060] Example 2 is repeated with the difference that the implant ismade of zirconium, having a zirconium oxide surface, and that thecompound according to formula (I) is ethane-1,1,3-triphosphonic acidwhich has been modified by linking the amine terminus of a Glycinemolecule to one of the phosphonate groups. Analogous test results areobtained as given in Table 1.

EXAMPLE 5

[0061] Examples 2 and 3 are repeated with the difference that thecompound according to formula (I) is the ethane-1,1,3-triphosphonic acidwhich is modified by linking the amine terminus of a GRGDS cell bindingpolypeptide to one of the phosphonate groups. Analogous results areobtained as given in Table 1.

EXAMPLE 6

[0062] Examples 2 and 3 are repeated with a the difference that thecompound according to formula (I) is ethane-1,1,3-triphosphonic acidwhich is modified by linking the amine terminus (Methionine) of a humanBone Morphogenic Protein type 2 (BMP-2) to one of the phosphonategroups, which gives analogous test results as given in Table 1.

1. Endosseous implant to be applied to a human or animal bone, saidimplant having a surface made from a selected metal or a selected metalalloy or a ceramic, whereby said metal resp. metal alloy is selectedfrom chromium, niobium, tantalum, vanadium, zirconium, aluminium,cobalt, nickel, stainless steels or an alloy thereof, said surfacehaving a smooth or rough texture, characterized in that said surface hasbeen treated with at least one pharmaceutically acceptable organiccompound carrying at least one phosphonic acid group or a derivativethereof, which is preferably a pharmaceutically acceptable ester, amideor salt thereof.
 2. Implant according to claim 1, characterized in thatthe surface of the implant is made of a ceramic selected from oxidesurfaces, carbide surfaces, nitride surfaces, oxynitride surfaces,carbonitride surfaces or oxycarbide surfaces of chromium, niobium,tantalum, vanadium, zirconium, aluminium, cobalt, nickel, stainlesssteels or alloys thereof.
 3. Implant according to claim 1, characterizedin that the surface of the implant is made of titanium carbide, titaniumnitride, titanium oxynitride, titanium carbonitride and/or titaniumoxycarbide.
 4. Implant according to claim 1, characterized in that thesurface of the implant is made of a metal oxide, preferably aluminiumoxide or zirconium oxide or silicon oxide, preferably from apatites,preferably hydroxyapatite or fluoroapatite, or apatite like materials,preferably tricalciumphosphate, or brushite type layers.
 5. Implantaccording to claim 1, characterized in that the surface of the implantis made of a glass like material, preferably silicate glass, or boronsilica glass, or bioglass.
 6. Implant according to any one of the claims1-5, characterized in that the surface of the implant has been treatedwith at least one organic compound, or a mixture of such compounds,corresponding to the general formula (I): A-[P(O)(OH)₂]_(p)  (I),or apharmaceutically acceptable derivative thereof, which is preferably apharmaceutically acceptable ester, amide or salt thereof, wherein Ameans A₁ or A₂, and A₁ is a residue of a linear, branched or cyclic,saturated or unsaturated, hydrocarbon residue with n carbon atoms,whereby said residue may be substituted by hydroxyl and/or carboxyl andoptionally further interrupted by one or more oxygen and/or sulphurand/or nitrogen atoms, carrying p phosphonic acid groups, wherein n is anumber from 1 to 70, preferably 1 to 40, preferably 1 to 22, and p is 1,2, 3, 4, 5 or 6, preferably 1, 2, 3, 4 or 5, preferably 1, 2, 3 or 4; oror A means A₂ and A₂ is a residue of an amino acid or of a sequence ofamino acids resp. of a protein or of a polypeptide, preferably a residueof the superfamily of Transforming Growth Factor beta (TGF-β); or aresidue of a specific drug molecule, wherein each residue A₂ carries pphosphonic acid groups, and p is 1 to 6, preferably 1, 2, 3 or 4,preferably 1, 2, or 3, when A₂ is a residue of an amino acid or of asequence of amino acids resp. of a protein or of a polypeptide; or p is1, 2, 3, 4, 5 or 6, preferably 1, 2 or 3, and preferably 1, when A₂ is aresidue of a specific drug molecule originally not bearing anyphosphonic group, optionally falling under the definition given for A₁ .7. Implant according to claim 6, wherein A has a meaning of A₁, and:when n is 1 and p is 2: A is —CH₂—; or when n is 1: p is 3 or 4,preferably 3; or when n is 2 to 10: p is 2, provided each phosphonicacid group or a derivative thereof preferablyor phosphonic acid estergroup is bound to a different carbon atom within the same molecule; orwhen n is 2 to 10: p is 3, 4, 5 or 6, preferably 3, 4 or 5, preferably 3or 4; or when n is 11 to 70: p is 2, 3, 4, 5 or 6, preferably 2, 3, 4 or5, preferably 2, 3 or
 4. 8. Implant according to claim 6, wherein A hasa meaning of A₂, and: p is 1 or 3-6, preferably 1, for the case that A₂is a residue of a specific drug molecule originally not bearing anyphosphonic group, optionally falling under the definition given for A₁.9. Implant according to claim 1, wherein A₁ is a saturated hydrocarbonresidue of the formula —(C_(n)H_(2n+2−)p)—, wherein n means 1 to 70,preferably 1 to 40, preferably 1 to
 22. 10. Implant according to any oneof the claims 1-9, characterized in that the compound of formula (I) isan alkali salt, preferably of sodium or potassium salt.
 11. Implantaccording to any one of the claims 1-10, characterized in that thecompound of formula (I) selected from a monophosphonic acid, preferablymethanephosphonic acid, ethanephosphonic acid, propanephosphonic acid ora polyphosphonic acid, preferably methylenediphosphonic acid,ethane-1,2-diphosphonic acid, propane-1,3-diphosphonic acid,propane-1,3-diphosphonic acid, ethane-1,1,2-triphosphonic acid,butane-1,1,4-triphosphonic acid, pentane-1,1,5-triphosphonic acid,pentane-2,2,5-triphosphonic acid, hexane-2,2,6-triphosphonic acid,pentane-1,1,5,5-tetraphosphonic acid, heptane-1,4,4,7-tetraphosphonicacid, propane-1,1,3,3-tetraphosphonic acid, ornonane-1,5,5,9-tetraphosphonic acid or from an unsaturatedmonophosphonic acid and polyphosphonic acid.
 12. Implant according toany one of the claims 1-11, characterized in that the pharmaceuticallyacceptable ester is the isopropyl phosphonate or ethyl phosphonateester.
 13. Implant according to claim 12, characterised in that theester is chosen from the group of tetra isopropylmethylenediphosphonate, hexaethyl ethane-1,1,2-triphosphonate,hexaisopropyl butane-1,1,4-triphosphonate, hexaisopropylpentane-1,1,5-triphosphonate, hexaisopropylpentane-2,2,5-triphosphonate, hexaisopropyl hexane-2,2,6-triphosphonate,octaisopropyl propane-1,1,3,3-tetraphosphonate, octaisopropylheptane-1,4,4,7-tetraphosphonate, octaisopropylnonane-1,5,5,9-tetraphosphonate.
 14. Implant according to claim 1,wherein the compound of formula (I) represents a Transforming GrowthFactor beta (TGF-β) as defined by the members of the superfamily ofgrowth factors, preferably the TGF-β1, TGF-β2, TGF-β3, TGF-β4, andTGF-β5, wherein each time the peptide chain has been modified to containat least one alkylphosphonic acid group or a derivative thereof, whichis preferably an ester, an amide or salt thereof.
 15. Implant accordingto claim 1, wherein the compound of formula (I) represents a BoneMorphogenic Protein (BMP), preferably the BMP-2 (BMP-2a), BMP-3, BMP-4(BMP-2b), BMP-5, BMP-6, BMP-7 (OP-1), BMP-8 (OP-2), BMP-9, BMP-10,BMP-11, BMP-12, BMP-13, wherein the peptide chain has been modified tocontain at least one alkylphosphonic acid group or a derivative thereof,which is preferably an ester, an amide or salt thereof.
 16. Implantaccording to claim 1, wherein the compound of formula (I) is selectedfrom 2-amino-4,4-bis-(diethoxy-phosphoryl)-butyric acid,2-amino-5-(diethoxy-phosphoryl)-pentanoic acid and/or2-amino-4-phosphonobutyric acid.
 17. Implant according to claim 1,wherein the compound of formula (I) is selected from one of theprincipal twenty amino acids, preferably arginine, glycine, asparticacid, alanine, valine, proline, serine, threonine, cysteine or lysine,wherein the amino acid has been modified to contain at least onealkylphosphonic acid group or a derivative thereof, which is preferablyan ester, an amide or salt thereof.
 18. Implant according to claim 1,wherein the compound of formula (I) is a RGD-containing peptide,preferably a RGDS-peptide, a GRGDS-peptide, a RGDV-peptide, aRGDE-peptide, and/or a RGDT-peptide, which has been modified to containat least one alkylphosphonic acid group or a derivative thereof, whichis preferably an ester, an amide or salt thereof.
 19. Implant accordingto claim 1, wherein the compound of formula (I) is selceted from1-hydroxy-3-(1-pyrrolidinyl)-propylidene diphosphonic acid,cycloheptylaminomethylene diphosphonic acid,1-hydroxy-2-imidazo-(1,2-a)-pyridin-3-yl-ethylidene diphosphonic acid,1-hydroxy-2-(3-pyridinyl)-ethylidene diphosphonic acid,(4-chlorophenyl)thio-methylene diphosphonic acid,1-hydroxy-2-(1H-imidazole-1-yl)ethylidene diphosphonic acid and relatedcompounds.
 20. Process for producing the implant according to any one ofthe claims 1-19, characterized in that said surface is treated with atleast one pharmaceutically acceptable organic compound of formula (I) ora salt or ester or an amide thereof.
 21. Implants according to any oneof the claims 1-20 in the form of screws, plates, nails, pins, andspecially formed parts and may be used as prostheses in medicine, morespecifically in orthopaedics, for replacing or strengthening broken ordiseased bones, and in dentistry, for anchoring artificial teeth or foranchoring of bone anchored hearing prosthesis into the skeletalstructure of humans and animals.
 22. Implant according to claim 21,characterized in that said implant is packed with a plastic or metallicpackaging material, preferably into an air tight packaging whichoptionally is evacuated or filled with an inert gas or an inert liquid.23. Implant according to claim 22, characterized in that said packagingis filled with pure water containing an inorganic salt and/or a compoundof the formula (I) or a salt or ester thereof, preferably in aconcentration of from about 1.0×10⁻⁵ mol/10 ml to 5×10⁻² mol/10 ml,preferably from about 5×10⁻⁴ mol/10 ml to 2.0×10⁻² mol/10 ml of thewater.
 24. The compounds according to formula (I) the salts or estersthereof according to any one claim of 1-19, wherein p is 3 to 6,preferably 3 or 4, and n is 4 to 70, preferably 4 to 40, preferably 4 to22.
 25. The compounds according to claim 24, beingbutane-1,1,4-triphosphonic acid, pentane-1,1,5-triphosphonic acid,pentane-2,2,5-triphosphonic acid, hexane-2,2,6-triphosphonic acid,pentane-1,1,5,5-tetraphosphonic acid, heptane-1,4,4,7-tetraphosphonicacid, or nonane-1,5,5,9-tetraphosphonic acid, a salt or an ester or anamide thereof.
 26. Process for producing the chemical compound in theform of their acid according to claim 24 and 25, characterized in thatthe corresponding ester is hydrolysed in the presence of an acid.